Surgical interventions often involve the implantation of a medical device, typically manufactured from polymeric and/or metallic materials, that is intended to provide a mechanical repair of a medical malady. While providing necessary and often life saving benefits, the implanted metal or polymer material may also produce some type of complication. Some of the more common complications include acute thrombosis; increased risk of infection immediately post procedure and/or chronically; fibrous encapsulation of the device resulting from a foreign body response and inflammation; and vascular proliferative disease resulting in an excessive, inflammatory, fibroproliferative response to injury.
In some cases therapeutic agents are administered to ameliorate complications arising from the medical implant and the disease being treated. Most often these are administered orally or through injection and result in systemic delivery. Ideally therapeutic agents would be released locally in a controlled fashion from an implant to maximize the effectiveness of the agent at the desired site without causing severe systemic side effects. A combination device, or product, that provides for local drug delivery and a mechanical solution to the medical malady may result in clinical outcomes not possible otherwise. One approach to achieving this combination is through the use of coatings applied to the surfaces of medical devices, implantable for short or long terms, wherein the coating may optionally contain therapeutic agents elutable from the coating.
Many systemic pharmacological approaches to reducing restenosis have been proposed including the use of various agents such as anticoagulants, antiplatelet agents, metalloprotease inhibitors, antiproliferative agents and anti-inflammatory agents. Many of these compounds have demonstrated some level of positive effect in animal models of restenosis. Unfortunately, the clinical application of these compounds has shown no positive indications. This ineffectiveness may be largely attributed to the inability of systemic delivery to provide effective drug concentrations at the desired site. The dose and manner in which these compounds are administered is suboptimal, necessitating the development of new delivery modalities, technologies, and materials to accomplish effective localized delivery. Furthermore, potentially useful but toxic agents that would otherwise not be considered because of problematic systemic concentration from injections or oral dosage forms, could be used in combination products with an effective localized delivery system.
While there is large potential for combination products that provide therapeutic delivery with medical devices, development has been slow. For example, the use of localized stent-based drug delivery to reduce restenosis has only recently been demonstrated in limited clinical trials. Many of the drugs being proposed for use in these combination devices have existed for many years. Paclitaxol is a prime example as it has long been used as a cancer therapy, and its effects on vascular cells have been known for some years. The slow emergence of these combination products then appears to be due to the lack of adequate materials to combine the drug and device into one medical embodiment that meets all the needs for clinical applications. Each combination product requires a suitable drug, a robust medical device, and a means to combine these two elements together in a single entity. Most often a polymer coating has been proposed as the material to combine the drug and device into a single entity. Unfortunately, many of the materials currently available have numerous shortcomings.
There is a need for biocompatible materials that can adequately retain an efficacious dose, provide for prolonged drug release, and be incorporated into the mechanical device, in the simplest possible fashion, without compromising the device functionality. Moreover, the material would truly be exemplary if it provided more benefits to the combination product than functioning solely as a matrix for the release of a therapeutic agent. Preferably, this can be accomplished without the addition of still another component, such as an adhesive material or primer coatings, or without requiring surface modification of the medical device, but rather with the polymer material itself serving as a biocompatible adhesive with or without additives.
The utilization of biodegradable materials for drug delivery such as alpha hydroxy esters is well known. These compounds have glassy or rigid amorphous states that do not meet the flexibility requirements of combination implantable device. These materials have poor adhesive properties, particularly with regard to common materials used to manufacture medical devices such as various metals and polymers such as polytetrafluoroethylene (PTFE). The biodegradable nature of these materials requires judicious use so as not to create fragmentation of the material and possibly the device as they degrade.
Silicones are among the most widely used synthetic polymers that are intended to be non-biodegradable and are found in a variety of medical applications. They are sometimes used as a matrix material for elution of therapeutic agents, and as an elastomer they offer a good degree of flexibility. See, for example, U.S. Pat. No. 6,358,556 to Ding et al. Silicones consist of at least three components: an elastomer, silica reinforcing agent, and a volatile inhibitor to stop cross-linking. However, silicones have poor bonding strengths to many medical device substrate materials, and poor long-term in vivo tensile strength. They are less biocompatible than most fluoropolymers. Silicones absorb lipids and proteins over time, have a tendency to generate particulate debris over time, and exhibit poor abrasion resistance. Curatives in the vulcanized polymer can be problematic in that they may react with additive. Other problems are known to include cracking, swelling (generally due to lipid or protein absorption), tear propagation and poor adhesion. These problems are exacerbated by the use of additives.
Various fluoropolymer materials have been proposed as drug delivery material; see, for example, EP 950386 to Llanos et al. which suggests a list of materials including PTFE. While PTFE is particularly inert and highly biocompatible, it is not elastomeric and is limited in elution capability if not used in its porous expanded form (ePTFE). Drugs are typically eluted from the interconnected void spaces of ePTFE rather than by molecular diffusion from within the polymer matrix; see, for example, U.S. Pat. No. 5,290,271 to Jemberg. EP 1192957 to Llanos et al., proposes other fluoropolymer materials comprising a first monomer chosen from the group consisting of vinylidene fluoride and a second monomer that is different from the first monomer. These materials are relatively non-durable according to examples that describe cracking of the matrix during device expansion. Likewise, these particular materials are limited in their drug loading and drug elution capabilities. The ability to bond to a variety of other materials without requisite primer coating or surface treatment of the substrate, the ability to function as an integral component of a coated medical device (without adverse effect on the device function), and the ability to aid in the manufacturing of a wide range of combination products has not been shown